In diseases such as osteoarthritis and rheumatism, a destruction of the joint takes place, with this being due, in particular, to the proteolytic breakdown of collagen by collagenases. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. The MMP's form a group of Zn-dependent enzymes which are involved in the biological breakdown of the extracellular matrix (D. Yip et al. in Investigational New Drugs 17 (1999), 387-399 and Michaelides et al. in Current Pharmaceutical Design 5 (1999) 787-819). These MMPs are able, in particular, to break down fibrillar and nonfibrillar collagen and also proteoglycans, both of which are important constituents of the matrix. MMPs are involved in processes of wound healing, of tumor invasion and metastasis migration as well as an angiogenesis, multiple sclerosis and heart failure (Michaelides, page 788; see above). In particular, they play an important role in the breakdown of the joint matrix in arthrosis and arthritis, whether this be osteoarthrosis, osteoarthritis and rheumatoid arthritis.
Furthermore, the activity of the MMPs is essential for many of these processes which play a role in atherosclerotic plaque formation, such as infiltration of inflammatory cells and smooth muscle cell migration, as well as proliferation and angiogenesis (S. J. George, Exp. Opin. Invest. Drugs (2000), 9 (5), 993-1007). In addition, matrix degradation by MMPs can give rise to anything from plaque instabilities to ruptures, with this in turn being able to lead to the clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E. J. M. Creemers et al., Circulation Res. 89, 201-210 (2001)). Seen as a whole, the entire MMP family is able to break down all of the components of the extracellular matrix of the blood vessels; their activities are therefore strictly regulated in normal blood vessels. The increase in MMP activity during plaque formation and plaque instability is brought about by an increase in cytokine-stimulated and growth factor-stimulated gene transcription, an increase in zymogen activation and an imbalance in the MMP/TIMP (tissue inhibitors of metalloproteases) ratio. It therefore appears plausible that MMP inhibition or restoration of the MMP/TIMP balance would be of help in treating atherosclerotic disease. It is also becoming ever clearer that an increase in MMP activity is also at least a contributory cause of other cardiovascular diseases, in addition to atherosclerosis, such as restenosis, dilated cardiomyopathy and the myocardial infarction which has already been mentioned.
In experimental animal models of these diseases, it has been shown that marked improvements, for example with regard to the formation of atherosclerotic lesions, neointima formation, left ventricular remodeling, pumping performance dysfunction or infarction healing, can be achieved by administering synthetic inhibitors. In addition, reduced collagen damage, improved extracellular matrix remodeling and improved structure and function of cardiac muscle and blood vessels have been found when detailed tissue analyses have been carried out in a variety of preclinical studies using MMP inhibitors. Of these processes, the matrix remodeling processes and MMP-regulated fibroses, in particular, are regarded as being important components in the progress of cardiac diseases (infarction) (Drugs 61, 1239-1252 (2001)).
MMPs cleave matrix proteins such as collagen, laminin, proteoglycans, elastic or gelatin and also process (i.e. activate or inactivate), by means of cleaving, a large number of other proteins and enzymes under physiological conditions, which means that they play an important role in the entire organism while being of particular significance in connective tissue and bones.
A large number of different MMP inhibitors have been disclosed (EP 0 606 046; WO 94/28889; WO 96/27583; or Current Medicinal Chemistry 8, 425-74 (2001)).
Following the first clinical studies performed on humans, it has now been found that MMPs give rise to side-effects. The side-effects which are principally mentioned are musculoskeletal pains and arthralgias. The prior art clearly indicates that inhibitors which are more selective are expected to be able to reduce these side-effects (Yip, page 387, see above). Specificity towards MMP-1 is to be particularly emphasized in the connection since these undesirable side-effects evidently occur to a greater degree when MMP-1 is inhibited.
A frequently occurring disadvantage of the known MMP inhibitors is therefore their lack of specificity. Most MMP inhibitors inhibit many MMPs simultaneously because the catalytic domains of the MMPs have similar structures. As a consequence, the inhibitors act in an undesirable manner on the enzymes, including those that have a vital function (Massova I, et al., The FASEB Journal (1998) 12, 1075-1095).